We propose a multidisciplinary, translational genetic study to identify genes that influence sensitivity to the stimulant drugs methamphetamine and amphetamine in mice and humans. We will use mice to better define chromosomal regions (also called quantitative trait loci or QTL) that contain genes that influence sensitivity to the acute locomotor stimulant effects of methamphetamine. This will be accomplished using two complimentary approaches: congenic strains, and advanced intercross lines. Using these techniques, we will be able to determine, with some precision, the location of genes that influence this trait. We will then use a variety of experimental and bioinformatic approaches to parse among the genes located in those regions, which will allow us to identify a small number of high probability candidate genes. We expect that this list of genes will include those responsible for differences in the response to methamphetamine in the mice. We will then explore the effect of polymorphisms in these genes on the subjective response to amphetamine in a sample of carefully screened, healthy human volunteers. All volunteers will give informed consent prior to participation in the study. We will use a double-blind, within-subject design in which each subject receives each dose (placebo, 5,10 and 20 mg) of amphetamine once, in a randomized order, over the course of 4 sessions. During the sessions when drug or placebo has been administered, subjects will self-report their emotional and cognitive experiences, which are expected to include a subjective feeling of being under the influence of a drug, as well as varying degrees of euphoria and anxiety. We will also evaluate their performance on behavioral tasks, and record physiological data over the course of the sessions. We will then examine the relationship between the response to amphetamine and polymorphisms in the genes selected in the mouse studies. We expect that some of the genes have polymorphisms that are associated with, and may cause, differences in the response to amphetamine among the human volunteers. We believe that differences in the acute response to stimulant drugs like amphetamine, methamphetamine and cocaine are important for determining the genetic risk for the development of drug abuse. Identification of these genes may be useful for developing new therapeutic strategies to treat or prevent drug abuse and addiction.